1. Technical Field
The present invention relates generally to herpesvirus vaccine compositions. In particular, the invention pertains to vaccines containing VP22 polypeptides and methods for treating and preventing herpes simplex virus infections using the vaccines.
2. Background of the Invention
Herpes simplex virus (HSV) infections are extremely prevalent and have a range of manifestations from apparently asymptomatic acquisition to severe disease and life-threatening infections in the immunocompromised individual and the neonate. These infections are caused by two viruses, herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). HSV-1 is the predominant cause of oral infections and is usually acquired in childhood, whereas HSV-2 infections are usually sexually transmitted genital infections. These distinctions are blurred, however, and up to 25% of genital herpes is caused by HSV-1. Following initial infection, the virus establishes a life-long latent state and periodically reactivates, causing clinically apparent lesional episodes or asymptomatic virus shedding.
Despite the availability of the antiviral agent, acyclovir, the incidence of HSV-2 in the population ranges from 8-50% and is increasing. The apparent reason for this increase is that most individuals are unaware of their infection. Moreover, the majority of transmission occurs from virus shed asymptomatically.
In general, HSV is a double-stranded DNA virus having a genome of about 150-160 kbp. The viral genomes of HSV-1 and HSV-2 are colinear and share greater than 50% homology over the entire genome. For some genes, the amino acid identity between the two virus types is as much as 80 to 90%. As a result of this similarity, many HSV-specific antibodies are cross-reactive for both virus types.
The viral genome is packaged within an icosahedral nucleocapsid which is enveloped in a membrane. The membrane (or envelope) includes at least 10 virus-encoded glycoproteins, the most abundant of which are gB, gC, gD, and gE. The viral glycoproteins are involved in the processes of virus attachment to cellular receptors and in fusion of the viral and host cell membranes to permit virus entry into the cell. As a consequence of their location (on the surface of the virion) and their role, the glycoproteins are targets of neutralizing antibody and antibody dependent cell cytotoxicity (ADCC) antibody. Within a virus type, there is a limited (1 to 2%) strain-to-strain sequence variability of the glycoprotein genes. The viral genome also encodes over 70 other proteins, including VP16 and VP22 which are associated with the virion tegument, located between the capsid and the envelope. (VP stands for xe2x80x9cvirion protein.xe2x80x9d)
One approach to HSV vaccine development has been the use of isolated glycoproteins which have been shown to be both protective and therapeutic. See, e.g., Burke et al., Virology (1991) 181:793-797; Burke et al., Rev. Infect. Dis. (1991) 13(Suppl 11):S906-S911; Straus et al., Lancet (1994) 343:1460-1463; Ho et al., J. Virol. (1989) 63:2951-2958; Stanberry et al., J. Infect. Dis. (1988) 157:156-163; and Stanberry et al., (1987) J. Infect. Dis. 155:914-920; Stanberry, L. R. xe2x80x9cSubunit Viral Vaccines: prophylactic and therapeutic use.xe2x80x9d In: Aurelian L (ed.) Herpesviruses, the Immune Systems and Aids. Kluwer, Boston, pp. 309-341. Similarly, the use of VP16 in vaccine compositions has recently been described. See, EP Publication No. 541,692. In addition, T-cell clones recovered from herpetic lesions have been shown to be reactive with VP16 (see, Koelle et al., J. Virol. (1994) 68:2803-2810).
There is growing evidence that vaccination against a number of viruses should target both the cellular and humoral arms of the immune system. In this regard, cytotoxic T-lymphocytes (CTLs) play an important role in cell-mediated immune defense against intracellular pathogens and in particular against viruses. CTLs mediate cytotoxicity of virally infected cells by recognizing viral determinants in conjunction with class I MHC molecules displayed by the infected cells. Cytoplasmic expression of proteins is generally considered to be a prerequisite for class I MHC processing and presentation of antigenic peptides to CTLs. Immunization with subunit glycoprotein vaccines may fail to effectively produce the CTLs necessary to curb intracellular infection.
Accordingly, the wide spread availability of an efficacious vaccine against HSV, able to elicit a cellular immune response, would therefore be highly desirable.
The present invention provides a method for treating and preventing HSV infection, as well as compositions for use in the method. In particular, the compositions include polypeptides derived from the viral tegument protein VP22 which, as shown herein, are able to elicit a cellular immune response. The compositions can include additional HSV polypeptides, such as HSV glycoproteins and VP16. In this way, immunization will elicit both cellular and humoral immunity and provide an extremely efficacious method for protecting against and treating HSV infection.
Accordingly, in one embodiment, the subject invention is directed to a subunit vaccine composition comprising a HSV VP22 polypeptide which is capable of eliciting a cellular immune response in a mammalian subject, and a pharmaceutically acceptable excipient. The VP22 polypeptide may be derived from HSV-1 or HSV-2. Alternative embodiments are directed to compositions which additionally comprise HSV VP16 polypeptides and/or HSV glycoproteins.
In another embodiment, the invention is directed to a method of producing a composition for the treatment or prevention of HSV infection comprising:
(a) providing an isolated VP22 polypeptide which is capable of eliciting a cellular immune response in a mammalian subject; and
(b) formulating the VP22 polypeptide with a pharmaceutically acceptable excipient.
In yet another embodiment, the subject invention is directed to a method for treating or preventing HSV infection in a mammalian subject comprising administering a composition as described above, to the subject. The composition can be administered prior to, and/or subsequent to, primary infection.
In a further embodiment, the invention is directed to a viral vector comprising a gene encoding a HSV VP22 polypeptide capable of eliciting a cellular immune response in a mammalian subject. The gene may be derived from HSV-1 or HSV-2.
In yet another embodiment, the subject invention is directed to a method for treating or preventing HSV infection in a mammalian subject comprising administering a viral vector as described above, to the subject.
In still a further embodiment, the invention is directed to a vaccine composition comprising a recombinant vector which comprises a gene encoding a HSV VP22 polypeptide operably linked to control elements that direct the transcription and translation of the gene in a mammalian host cell, and a pharmaceutically acceptable excipient. The gene encoding the VP22 polypeptide may be derived from HSV-1 or HSV-2 and the vector can be a nonviral or a viral vector.
In yet another embodiment, the subject invention is directed to a method for treating or preventing HSV infection in a mammalian subject comprising administering the composition above.
These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.